WO1995001974A1 - Piperidinyl substituted methanoanthracenes as d1/d2-antagonists and 5ht2-serotanin-antagonists - Google Patents
Piperidinyl substituted methanoanthracenes as d1/d2-antagonists and 5ht2-serotanin-antagonists Download PDFInfo
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- WO1995001974A1 WO1995001974A1 PCT/GB1994/001439 GB9401439W WO9501974A1 WO 1995001974 A1 WO1995001974 A1 WO 1995001974A1 GB 9401439 W GB9401439 W GB 9401439W WO 9501974 A1 WO9501974 A1 WO 9501974A1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/40—Oxygen atoms
- C07D211/44—Oxygen atoms attached in position 4
- C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the present invention relates to novel piperidinyl compounds which contain a chiral sulfoxide moiety and processes related to their synthesis and production.
- the compounds and the pharmaceutical compositions containing the active ingredient are useful as dopamine antagonists and are particularly useful as antipsychotic agents in humans.
- the compounds may also be useful in other neurological and psychiatric disorders including schizophrenia.
- methanoanthracenyl compounds that are essentially or substantially pure chiral sulfoxide enantiomers or diastereomers and pharmaceutical compositions containing said active ingredients wherein the compounds are useful as D1 and D2 dopamine antagonists as well as 5HT2 serotonin antagonists.
- the claimed compounds have an improved, balanced and more favorable D1/D2 dopamine antagonist ratio which may be predictive of an improved clinical profile in humans.
- the present compounds are also serotonin 5HT2 antagonists.
- the present invention also relates to novel syntheses of chiral methanoanthracenyl sulfoxides wherein the process utilizes several oxidation methods to selectively oxidize a methanoanthracenyl sulfide to an enantiomerically enriched sulfoxide mixture which can be further purified to a pure or substantially pure methanoanthrancenyl sulfoxide.
- the present invention relates to a process for recycling racemic materials or those enriched in the undesired methanoanthrancenyl sulfoxide enantiomer which may be readily coupled with the enantioselective oxidation to produce pure enantiomeric material.
- the present invention relates to novel methanoanthrancenyl piperidinyl sulfoxide compounds and their pharmaceutically acceptable salts of the formula as described and set out on the first page following the Examples section wherein the various groups on the formula I (X, Y and R1) are defined as follows:
- X and Y are independently selected from hydrogen, halogen and C1-6 alkoxy;
- R1 is selected from:
- six-membered heteroaryl ring is a chiral sulfoxide of the formula C 1-4 alkylSO.
- the invention further provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula I as defined above and shown on the pages following the examples and to pharmaceutically acceptable salts thereof and a pharmaceutically acceptable diluent or excipient.
- the claimed composition may be administered to a patient in need of treatment thereof in a suitable dosage form via an effective delivery system to provide D1 and D2 dopaminergic antagonist activity and to relieve or treat or prevent neurological and psychiatric disorders wherein antipsychotics are a prescribed treatment.
- the invention further provides a method of treating neurological disorders comprising administering to a patient in need of treatment thereof a pharmaceutically effective amount of a compound according to formula I or a pharmaceutically acceptable salt thereof.
- invention also relates to a method of treating psychosis comprising administering a pharmaceutically effective amount of a pharmaceutical composition containing an active ingredient as described in formula I and a pharmaceutically acceptable carrier or diluent.
- the invention further relates to a method of antagonizing a D1 and D2 dopamine receptor in humans comprising administering an antipsychotic amount of the compound according to formula I or a pharmaceutical composition containing the compound of formula I as the active ingredient.
- alkyl and alkoxy include both straight and branched chain radicals, but it is understood that references to individual radicals such as “propyl” or “propoxy” embrace the straight chain radical and branched chains such as
- halo is inclusive of fluoro, chloro, bromo, and iodo unless otherwise specified.
- hydroxy is given its ordinary meaning and may be included as a substituent as further shown herein.
- Particular values of C 1-6 alkyl include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and isohexyl.
- Particular values of C 1-3 alkyl include methyl, ethyl, and propyl.
- C 1-6 alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexoxy, and isohexoxy.
- Particular values of C 1-3 alkoxy include methoxy, ethoxy, and propoxy.
- Particular values of five- and six-membered heteroaryl rings containing from 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur include 2, 3- and 4-pyridyl, 2-pyrazinyl, 2- and 4-pyrimidinyl, 3- and 4-pyridazinyl, 3-, 4- and 5-isothiazoyl, 2-, 4- and 5-oxazolyl, 2-, 4- and 5-thiazolyl, 4- and 5-oxadiazoyl, 2- and 3-furyl, 2-, 4- and 5-imidazolyl, and 2- and 3-thienyl.
- the preceding rings can optionally bear the substituents listed above in the preceding paragraphs.
- benz derivatives of five- and six-membered heteroaryl groups include the various quinolinyl, isoquinolyl, and benzothiazolyl groups which may also be substituted with halo or C 1-6 alkyl or alkoxy groups as shown above.
- C 1-6 hydroxyalkyl include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-3 hydroxypropyl, l-hydroxyprop-2-yl, and 1-3 hydroxybutyl.
- X and Y include hydrogen and halo. More particular values of C 1-6 alkyl include C 1-4 alkyl, including methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and isobutyl.
- C 1-6 alkyloxy include values of C 1-4 alkoxy, including methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert-butoxy.
- More particular values of five- and six-membered heteroaryl rings containing from 1-3 heteroatoms selected from nitrogen, oxygen and sulfur include 2, 3-, and 4-pyridyl, 3-, 4- and 5-isothiazoyl, 2-, 4- and 5-thiazoyl, and 2- and 4-imidazoyl wherein the rings may optionally be substituted with the substituents as defined above.
- More particular values of benz derivatives of five- and six-membered heteroaryl groups include 3-quinolyl,
- C 1-6 hydroxyalkyl More particular values of C 1-6 hydroxyalkyl include values of C 1-3 hydroxyalkyl such as hydroxymethyl, 1 or 2
- X and Y as defined herein are hydrogen and chloro with hydrogen being most preferred.
- R 1 is as a six-membered heteroaryl ring substituted with 1-2
- substituents and particularly includes 3-pyridyl substituted at the 2-position with C 1-4 alkylsulfinyl wherein the C 1-4 alkylsulfinyl lends chirality to the preferred compounds described herein.
- a preferred compound may be selected from formula I as shown following the examples wherein:
- X and Y are hydrogen; R 1 is 3-pyridyl substituted at the 2-position with C 1-4 alkylsulfinyl.
- a specifically preferred compound is
- the present invention also includes enantiomeric mixtures of the above preferred compound wherein the (-) enantiomer is present in excess over the (+) enantiomer.
- stereochemistry may be preferred.
- the stereochemistry can be determined by standard methods such as coupling an acid chloride at the 9-position of the methanoanthracene ring with a chiral resolving reagent to produce a mixture of diastereomers which can be separated by recrystallization or via high performance liquid chromatography ("HPLC") or other chromatographic methods to produce the pure diastereomer whose absolute stereochemistry can then be determined.
- HPLC high performance liquid chromatography
- Diastereomeric adducts may also, in some circumstances, be separated by fractional crystallization.
- the compounds produced and claimed herein may be selectively produced by chiral oxidation means of a sulfide moiety present on the described heteroaryl rings.
- the selective oxidation of the sulfide moiety to produce an enantiomerically enriched mixture wherein one enantiomer predominates as further described herein may also be coupled to a recycling process whereby the non-desired sulfinyl enantiomer may be reduced and reoxidized to form additional desired product.
- a compound of formula I may readily be obtained by synthetic methods described herein.
- An alkylthio moiety may be prepared prior to the chiral oxidation and/or recycling procedure.
- a process for preparing a compound of formula I may proceed as follows:
- the lithium compound can be conveniently generated in situ by reacting a compound of formula R 1 Z, wherein Z is a halo group or, in some cases hydrogen, with a C 1-6 alkyl lithium compound such as n-butyl lithium in a temperature range of -20 to -100 degrees C; the compound produced after coupling of the heteroaryl anion to the 4-piperidone methanoanthracenyl species is preferrably utilized as an intermediate (which is also part of the invention) which is further modified to form a compound of formula I wherein a C 1-4 alkylthio moiety is basified (to form an anion) and reacted with a leaving group on the five and/or six-membered heterocyclic ring wherein the
- alkylhalide to form the alkoxy compound(s).
- a suitable oxidising agent which (as mentioned below) include, for example, a titanium/tartarate/peroxide mixture such as a mixture of a titanium alkoxide (eg. titanium tetraisopropoxide), a dialkyl tartarate (eg. diethyl tartarate) and an alkyl hydroperoxide (eg. t-butyl hydroperoxide).
- suitable oxidising agents include chiral oxaziridine such as (S)-(+)-camphorsulfonyl oxaziridine, and suitable enzymes.
- the reation is generally carried out in an inert hydrocarbon solvent such as toluene and is conveniantly carried out with cooling eg. in the range -78oC to ambient temperature.
- the present invention relates to a process for producing a compound of formula I (as shown in the first page
- X and Y are independently selected from hydrogen, halogen and C1-6 alkoxy;
- R1 is selected from:
- six-membered heteroaryl ring is a chiral sulfoxide of the formula C 1-4 alkylSO; said process comprising the steps of:
- ethanoanthracene acetoxy aldehyde of formula 16 or equivalent C 1-4 alkyl carbonyloxy aldehyde which is then treated with an oxidizing agent selected from CrO 3 /H 2 SO 4 in H 2 O/acetone or an equivalent oxidizing reagent or system to form a corresponding 9-carboxylic acid shown as 15 or equivalent C 1-4 alkyl carbonyloxy acid which is then treated with a diarylphosphoryl azide and a trialkylamine in a suitable solvent such as methylisobutylketone or equivalent to form a corresponding acyl (or C 1-4 alkyl carbonyloxy) azide as a key
- the 9-carboxylic acid 15 or equivalent is treated with SOCl 2 , DMF in toluent to form an intermediate acid halide which is then treated with NaH 3 (1.5 eq) to form the intermediate and corresponding azide which is then heated to form an isolable
- the intermediate isocyanate is acidified with an acetic acid/HCl mixture in a solvent such as toluene or its equivalent to form the primary amine 20; the free amine produced in the alternative steps is then ring contracted via a carbocation intermediate to form 22;
- R is equal to a five- and/or six-membered heteroaryl ring selected from: Five- and six- membered heteroaryl rings containing from 1-3 heteroatoms selected from nitrogen, oxygen, and sulfur, and benz derivatives thereof, which may bear 1-2 substituents selected from C1-6 alkyl, hydroxy, C1-6 alkoxy which may bear a trifluoromethyl group, C1-6 alkoxycarbonyl, C1-6 hydroxyalkyl, benzyloxy, halo, C1-3 alkylaminocarbonylC1-3alkyl, aminocarbonyl having the formula: CONR c R d wherein R c and R d are independently selected from hydrogen,
- R e S(0) n , R f NH, and R g S wherein R e and R f are independently selected from hydrogen and C 1-6 alkyl and n is 0, 1 or 2 and R g is selected from C 1-3 alkylcarbonylaminophenyl and di(C 1-3 )alkylamino(C 1-6 )alkyl wherein at least one of the substituents on the five- and/or
- six-membered heteroaryl ring is a suitable leaving group which may be displaced by a C 1-4 alkylthio nucleophile
- step (e) reacting a compound produced in step (d) above with an enantioselective oxidizing agent under suitable conditions to form a compound of formula I.
- the preferred compound produced in the above process and utilized in the pharmaceutical compositions of the invention is the crystalline form of (-)-1-(9,10-Dihydro-9,10
- the above preferred enantiomer is preferrably utilized as an antipsychotic.
- methanoanthracen-9-ylmethyl)-4-2-ethylsulfinyl-3-pyridyl)piperidin-4-o 1 for the treatment of psychoses in human patients is a feature of the claimed invention characterized in that the crystalline compound is an antagonist of the D1/D2 dopamine receptors and the 5HT2 serotonin receptor.
- This balanced profile is predicitive of an improved clinical profile since antipsychotic efficacy is achieved and side effects associated with D2 receptor antagonism are minimized.
- a preferred process for producing crystalline (-)-1-(9,10-Dihydro-9,10 methanoanthracen-9-ylmethyl)-4-2-ethylsulfinyl-3-pyridyl)piperidin-4-ol is a feature of the claimed invention and comprises the steps of:
- the intermediately isocyanate is acidified with an acetic acid/HCl mixture in a solvent such as toluene to form the amino alcohol 20 which is ring contracted via the carbocation intermediate to form 22;
- step (e) treating the 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(2-ethylthio-3-pyridyl)piperidin-4-ol generated in step (d) above with a cooled solution of diethyl D-tartrate in undried toluene or equivalent solvent; titantium tetraisopropoxide and t-butyl hydroperoxide to form an enantiomerically enriched ethylsulfinyl mixture which is then recrystallized in a suitable solvent such as MeCN or equivalent to form pure (-) enantiomer.
- a suitable solvent such as MeCN or equivalent
- a process for producing crystalline (-)-1-(9,10-Dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(2-ethylsulfinyl-3-pyridyl)piperidin-4-ol which comprises treating 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(2-ethylthio-3-pyridyl)piperidin-4-ol with a solution (preferably cooled) of diethyl D-tartrate in toluene (preferably undried) or equivalent solvent; titantium tetraisopropoxide and t-butyl hydroperoxide to form an enantiomerically enriched
- R 1 Z can be made by techniques similar to that described in Brandsma et al., Preparative Polar Organometallic Chemistry I, Springer-Verlag (1987).
- Et is ethyl
- THF is tetrahydrofuran
- Bu is tert-butyl
- RT room temperature
- DMSO dimethylsulfoxide
- Me is methyl
- Cbz is carbobenzyloxy
- Ph is phenyl.
- Z is a halo group such as chloro when Grignard agents or alkyllithium compounds are described.
- a common intermediate for making compounds according to the invention is an acid (G is hydroxyl) or acid halide ( G is a halo group such as chloro) of formula III.
- This intermediate can be made as shown in Scheme 1 which is illustrated following the examples.
- An anthraquinone of formula 10 can be reduced to the corresponding anthracene of formula 12 using zinc and aqueous ammonia.
- Anthracene 12 can then be converted to the corresponding 9-aldehyde 14 using phosphorous oxytrichloride and N-methyl formanilide.
- Amine 20 can then be treated with an alkali metal nitrite (for example, sodium nitrite in acetic acid) to effect a ring contraction and thereby yield the 9-aldehyde of formula 22.
- Aldehyde 22 can then be oxidized with, for example, chromium trioxide in the presence of sulfuric acid, to yield the corresponding acid of formula 24
- the corresponding 9-acid halide such as the acid chloride may then be obtained by treating acid 24 with thionyl halide (thionyl chloride) or oxalyl halide (chloride).
- 2,7-dihalo alkyl ester by reaction with a diazotizing agent such as tert-butyl nitrite followed by treatment with cupric halide.
- the ester can then be cleaved with a suitable base (such as alkali metal hydroxide) to afford the corresponding 2,7-dihalosubstituted acid.
- an oxygenated substituted methanoanthracene e.g. 2-halo-7 alkoxy
- it can be prepared staring with the 7-amino-2-halo compound(s) described above.
- the amine is treated with a diazotizing agent such as tert-butyl nitrite followed by treatment with the salt of a suitable acid such as trifluoroacetic acid (the salt being formed, for example, with potassium carbonate in trifluoroacetic acid as the solvent).
- a suitable acid such as trifluoroacetic acid
- An amide of formula Ha can be made by treating an acid chloride of formula III (G is halo) with a piperidine of formula IV in the presence of a base such as a trialkylamine, for example triethylamine.
- a piperidone of formula II can be made, as illustrated in Scheme 2 by oxidizing a corresponding hydroxypiperidine of formula 32 using an appropriate oxidizing agent such as (1) chromium trioxide in the presence of sulfuric acid and using a suitable solvent such as acetone; (2) sulfur trioxide-pyridine complex in the presence of a base such as trialkylamine (e.g.
- a suitable solvent such as a combination of methylene chloride and DMSO; or (3) a combination of oxalyl chloride and DMSO followed by treatment with a base such as a trialkylamine and using a solvent such as methylene chloride.
- a hydroxypiperidine of formula 32 can be made by either of the routes illustrated in Scheme 2.
- 9-aldehyde 22 can be treated directly with 4-hydroxypiperidine and sodium cyanoborohydride to yield the corresponding amine 32.
- 9-aldehyde 22 can first be oxidized and converted to the corresponding 9-acid chloride as previously described, followed by treatment with 4-hydroxypiperidine, wither in excess or with added base such as a trialkylamine (for example, triethylamine) to yield the corresponding amide 30.
- a trialkylamine for example, triethylamine
- Piperidines having formula IV can be synthesized as illustrated in Scheme 3. 4-hydroxypiperidine 50 can be reacted with
- Piperidone 54 can be treated with an organolithium compound R 1 Li wherein R 1 is as defined previously or a Grignard reagent R 1 MgZ, at a temperature of -20 to -70 degrees C and in a solvent such as THF or diethylether to yield the corresponding protected hydroxypiperidine 56.
- R 1 Li organolithium compound
- R 1 MgZ Grignard reagent
- the C 1-4 alkylthio derivatives used as precursors to the preferred chiral sulfoxides of the instant invention may readily be prepared according to the following basic procedure.
- a solution of, for example, 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(2-fluoro-3-pyridyl)piperidin-4-ol which is prepared from reacting the anion of 2-fluoropyridine with 1-(9, 10-dihydro-9, 10-methano-anthracen-9-ylmethyl)-4-piperidone and lithium bromide
- a suitable solvent such as THF
- the sodium alkylthiolate is readily prepared from the C 1-4 alkylthiol compound and sodium hydride under standard conditions.
- the reaction between the alkylthiolate and the 2-fluoro derivative is allowed to proceed under reflux for about a minimum of three hours and is subsequently quenched by pouring into water.
- the aqueous phase is extracted with ether or other suitable organic solvent and the resultant product is purified by suitable chromatographic means such as flash
- the selective oxidation procedure of the described alkylthio compounds may proceed as follows. To a cooled solution (-20 degrees C) of (-)-diethyl D-tartrate in a suitable solvent such as dry (anhydrous) toluene under a nitrogen atmosphere is added titanium tetraisopropoxide in a dropwise fashion. The mixture is stirred for about five minutes with the subsequent addition of an alkylthio derivative such as 1-(9, 10-dihydro-9,10-methanoanthracen-9- ylmethyl)-4-(2-ethylthio-3-pyridyl)piperidin-4-ol which is added in one portion.
- a suitable solvent such as dry (anhydrous) toluene under a nitrogen atmosphere
- titanium tetraisopropoxide in a dropwise fashion.
- an alkylthio derivative such as 1-(9, 10-dihydro-9,10-methanoanthracen-9- ylmethyl)-4-(2-
- the reaction is maintained at the above temperature for about 25 minutes and is then cooled to about -78 degrees C before the addition of freshly dried t-butyl hydroperoxide (in slight molar excess) via syringe.
- the reaction is allowed to warm to -15 degrees C over a several hour period (about 3 hours) and is then placed without stirring in a 15 degree freezer for about 18 hours.
- the reaction is then quenched by adding aqueous sodium hydroxide (about 1N).
- the suspension is then diluted with methylene chloride and the mixture is filtered through diatomaceous earth.
- the product is purified by chromatographic means such as flash chromatography to give an enantiomeric mixture of chiral sulfoxides wherein the enantiomeric ratio is about 1:3.7 of (+) C 1-4 alkylsulfinyl methanoanthrancenyl compound to (-) C 1-4 alkylsulfinyl methanoanthracenyl compound ( as determined by HPLC analysis of the enantiomers). Recrystallization of the product mixture in a suitable solvent such as hot toluene leads to an enantiomeric mixture with a ratio of 1:99 wherein the
- (-)-enantiomer predominates in the mother liquors. Crystallization of the mother liquor leads to a pure (-) -enantiomer as a crystalline solid.
- Scheme 4 depicts the specific chiral oxidation(s) of either the pyridyl ethyl thio compound or the heteroaryl (het) C 1-4 alkyl thio compound(s) to form the respective sulfinyl compound.
- het refers to the five and six membered heteroaryl rings as defined herein for Rl.
- the preferred enantiomer produced in this manner is (-)-1-(9, 10-Dihydro-9, 10-methanoanthrancen-9-ylmethyl)
- the present invention therefore relates to a process for producing chiral sulfinyl
- methanoanthracenyl compounds comprising the steps of (a) reacting a compound of the formula I wherein X and Y and R are as defined herein except R includes a C 1-4 alkylthio moiety with (b) an asymmetric oxidizing reagent selected from (1) titanium/tartrate/peroxide or (2) a chiral oxaziridine wherein the reaction proceeds enantioselectively to produce a chiral enantiomeric mixture of oxides of formula I.
- the present invention also relates to a process comprising the steps as described above plus an additional recrystallization to afford an enantiomerically pure sulfinyl enantiomer of formula I.
- the invention also encompasses those diastereomeric mixtures which result wherein at least one of the heteroaryl substituents is a chiral sulfinyl moiety and an additional chiral substituent is present on the heteroaryl group as defined herein or on the methanoanthracenyl nucleus.
- the present process produces significant enantiomeric excess and thus the present invention is directed to a novel process for producing enantiomeric methanoanthracenyl sulfoxides.
- a process for asymmetrically oxidizing aryl-alkyl sulfides of specific formulae to sulfoxides is described generally in Pitchen et al. J. Am. Chem. Soc. 1984, 106, 8188-8193.
- the present invention also relates to a process whereby the non-desired sulfoxide is reduced back to the sulfide which is then prepared for an additional enantioselective oxidation to produce the preferred enantiomer or diastereomer.
- a compound such as a) 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(C 1-4 alkylthio-3-heteroaryl)piperidin-4-ol derivative may be synthesized by reducing the corresponding C 1-4 alkylsulfinyl-3-heteroaryl derivative with a suitable reducing agent such as zinc dust/titanium tetrachloride.
- the preferred compound recycled in this manner is the racemate of or material containing the (+)-1-(9,10-dihydro-9,10-methanoanthrancen-9-ylmethyl)-4-(2-ethylsulfinyl-3-pyridyl)piperidin-4-ol which, after reduction, yields 1-(9,10)-dihydro-9,10-methanoanthrancen-9-ylmethyl)4-(2-ethylthio-3-pyridyl)piperidin-4-ol.
- this compound is then oxidized via the enantioselective process described herein to form additional (-)-enantiomer.
- the present invention relates to a selective and dual process for preparing specific enantiomers or diastereomers of C 1-6 alkylsulfinyl methanoanthrancenyl compounds via a selective oxidation and recycling procedure.
- This process yields specific enantiomers or diastereomers which are useful as D1/D2 dopamine receptor antagonists such as the preferred (-)-1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4 -(2-ethylsulfinyl-3-pyridyl)piperidin-4-ol compound.
- This compound has a surprisingly improved D1/D2 ratio which can generally be indicative of an improved clinical therapeutic profile in patients in need of treatment of disorder such as psychoses. Its D1 receptor antagonist activity is closer to its D2 receptor antagonist activity thus leading to a balanced D1/D2 profile which may be predictive of an improved clinical profile over conventional antipsychotic agents.
- the (-)-enantiomer has an improved D1/D2 profile over the racemate of the same chemical formula.
- Suitable pharmaceutically acceptable salts are organic addition salts formed with acids which form a physiologically acceptable anion, for example, tosylate, methansulfonate, acetate, tartrate, citrate, succinate, benzoate, ascorbate, fumurate, maleate, alpha-ketoglutarate, and alpha-glycerophosphate.
- Suitable inorganic salts may also be formed such as sulfate, nitrate, phosphate and hydrochloride.
- Pharmaceutically acceptable salts may be obtained using standard procedures well known in the art, for example, by reacting a compound of formula I with a suitable acid to afford a pharmaceutically acceptable salt.
- a compound of formula I or preferably the compound (-)-1-(9,10)-Dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(2-ethylsulfinyl-3-pyridyl)piperidin-4-ol is preferably used.
- This compound may be admixed with a pharmaceutically acceptable carrier or diluent and administered in a pharmaceutically effective amount to a patient in need of treatment thereof.
- the particular composition chosen may be dependent upon or adapted for the desired route of administration.
- these suitable pharmaceutical compositions are a further feature of the invention described herein.
- compositions may be obtained by utilizing conventional procedures and by incorporating conventional pharmaceutical binders, excipients, fillers, inert ingredients, disintegrants and the like.
- the active compounds and/or the pharmaceutical compositions described herein may be prepared in a variety of dosage forms depending upon the preferred route of administration.
- Oral dosage forms may include tablets, capsules, solutions or suspensions.
- Intravenous, intravesicular, subcutaneous, or intramuscular injection or infusion dosage forms may be in the form of sterile solutions or suspensions.
- Suppository compositions may be prepared if rectal administration is necessary.
- Oral administration is the preferred route of administration for soluble salts within the scope of the present invention.
- the less soluble free amines or non-salt forms within the scope of the present invention are administered to a patient in a sustained release or DEPOT formulation wherein the active ingredient is slowly released over a period of days or other suitable period to a patient in need of treatment thereof.
- the present invention therefore also relates to a method of
- a DEPOT formulation containing the described active ingredients may be administered by implantation (for example, subcutaneously, transcutaneously or intramuscularly) or by intramuscular injection. These formulations may therefore be formulated with pharmaceutical excipients such as suitable polymeric or hydrophobic materials (e.g. as emulsions in oil) or as a sparingly soluble salt.
- suitable polymeric or hydrophobic materials e.g. as emulsions in oil
- the dosages of the DEPOT formulation are chosen to administer a pharmaceutically effective amount of the described D1/D2/5HT2 antagonist over an extended period of time.
- a compound of formula I which is administered to a patient in need of treatment thereof will necessarily vary depending upon the particular patient and the severity of their condition and their body weight and particular biochemistry.
- a clinician or physician of ordinary skill in the art can readily determine the suitable dosage from the ranges described herein and from the patients particular characteristics.
- a compound of formula I will be administered to a patient in need of treatment thereof (such as man) so that a pharmaceutically effective amount is received and this dosage is generally in the range of about 0.01 to about 10 mg/kg body weight. If a drug is administered intramuscularly, it is administered in the range of about 0.01 to about 5 mg/kg body weight. If it is administered orally, it is administered in the range of about 0.1 to about 10 mg/kg body weight. It will be apparent to those skilled in the art that a compound of formula I can be co-administered with other therapeutic or prophylactic agents and/or medicaments that are not contraindicated therewith.
- the compounds of formula I are antagonists of both D1 and D2 dopamine receptors and therefore are useful as antipsychotic drugs.
- the compounds of formula I are useful as 5HT2 serotonin receptor antagonists and thus are further useful as antipsychotics. These compounds therefore have significant serotonin antagonist activity as well as a balanced D1/D2 profile.
- D1 and D2 and 5HT2 antagonism may be shown by standard tests as described below.
- D2 antagonism can be shown by standard tests such as antagonism of
- 5HT2 receptors and clearly show an improved and balanced receptor antagonist profile.
- Dopamine D-1 binding assays were carried out at 37°C for 15 minutes in 1.0 ml of 50 mM Tris-HCl containing 120 mM NaCl, 5 mM KCl, 2mM CaCl2 and 1 mM MgCl2
- IC50 values were determined from a least squares regression of a logit-log
- the K. values of, for example, racemic 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(2-ethylsulfinyl-3-pyridyl)piperidin-4-ol were 118 nM, 10 nM, and 21 nM for the D1, D2 and 5HT2 receptors respectively.
- the pure (about 100%) levorotatory isomer of the above compound gave 13 nM, 42 nM and 39 nM.
- each mouse was placed into a circular swimming tank for 2 min and the number of swims was counted.
- the height of the tank was 15 cm and the diameter was 28 cm.
- a circular obstacle measuring 10.5 cm in diameter and having a height of 17 cm was placed into the center of the tank, creating a circular swimming channel 8.75 cm wide.
- the water level was 5.5 cm and the water was kept at room temperature.
- Marks were placed on the floor and the side of the tank 180 degrees apart. A "swim" was scored each time a mouse swam from one mark to the other. The mice were observed through overhead mirrors and the number of 180 degree swims was recorded for each mouse. Activity in this test was indicated by a decrease in the climbing score
- results are expressed as ED50s for climbing and swimming,.i.e., dose at which there was a 50% decrease in climbing and dose at which there was a 50% increase in swimming.
- Typical results for climbing and swimming respectively were ED50s of 0.54 and 1.7 mg/kg po for the racemate described above and 1.3 and 1.6 mg/kg po for the pure levorotatory isomer.
- racemate described above had an - IC50 value (drug concentration which produced a 50% inhibition of SKF 38393-induced rotations) of 3.95 mg/kg (i.p.) and the member of the heteroaryl C 1-4 alkyl sulfinyl class described above ( 95% pure C 1-4 alkyl sulfinyl levorotatory isomer) had an IC50 value of 1.98 mg/kg (i.p.).
- temperatures are given in degrees Celsius (C); operations and/or reactions were carried out at room or ambient temperature, that is, in the range of 18-25 °C.
- HPLC High pressure liquid chromatography
- HPLC analyses for most reactions and final products was carried out on either a 25cm ⁇ 4.6 mm Supelcosil LC-8-DB, a 25 cm ⁇ 4.6 mm Supelcosil LC-18-DB column available from Supelco, State College, PA, USA or a 25 cm x 4.6 mm Zorbax RX column.
- melting points are uncorrected and (dec) indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymorphism may result in isolation of materials with different melting points in some preparations;
- the product was purified by flash chromatography over silica gel (50 mL, eluent: 10% methanol/ethyl acetate) to yield 93 mg (45 %) of the title compound as a yellow/white solid.
- the enantiomeric purity of this compound was determined to be 1:5.6 ((+):(-)) by HPLC analysis.
- the (-)-isomer could be further enriched by the procedure described above.
- the starting piperidin-4-ol was prepared as follows: a. 9,10-Dihydro-9,10-methano-9-anthracenecarboxylic acid
- the reaction containing a significant amount of reduced chromium salts, was warmed to room temperature.
- the solvents were removed in vacuo and replaced with water (300 mL) and saturated with sodium chloride.
- the aqueous phase was extracted with ethyl acetate (3 ⁇ 300 mL).
- Combined organic extracts were extracted with 2.5 N NaOH (3 ⁇ 400 mL).
- the basic aqueous extracts were acidified with 3 N HCl, saturated with sodium chloride, and extracted with ethyl acetate (4 ⁇ 300 mL).
- Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to a white solid.
- the title compound was formed in 80% yield as a white solid.
- reaction product was purified by flash chromatography over silica gel (200 mL, eluent: 50% ether in hexane) to yield 2.00 g (90%) of the title compound. TLC analysis (R f 0.29, 50% ether in hexane).
- Zinc dust (1.72 g, 26.2 mmol) was transferred under nitrogen to a dry 500 mL roundbottom flask equipped with a nitrogen inlet, addition funnel, teflon coated magnetic stirbar and thermocouple.
- Distilled tetrahydrofuran (200 mL, from sodium/benzophenone ketyl) was added to the reaction vessel via cannula and the resulting suspension cooled to 0° C with an ice bath. Titanium tetrachloride (1.44 mL, 13.1 mmol, recently distilled) was added to the vortex of the rapidly stirred zinc suspension to reduce splattering. The initially formed titanium tetrachloride-tetrahydrofuran complex (yellow) quickly dissipates as reaction with the zinc takes place.
- the aqueous phase was extracted with ethyl acetate (2 X 250 mL). Combined organic extracts were dried over anhydrous sodium sulfate, filtered and reduced to an oil. TLC analysis (Rf 0.29, 50% ether in hexane) indicated the presence of product only.
- the reaction product was purified by dissolving the residue in hot toluene (10 mL) and diluting it with hot hexane (20 mL). After brief heating to reflux, this solution was filtered and cooled to room temperature. After the sulfide crystallization appears to have peaked, the recrystallization system was cooled to 0° C.
- the starting -2-(ethylthio-3-pyridyl)-piperidin-4-ol compound was advantageously prepared as follows: a. 9-formyl-9,10-dihydro-9,10-methanoanthracene.
- a tablet preparation may be composed of the above compound(s) (50.0 mg) for therapeutic or prophylactic use in humans and may also contain pharmaceutically acceptable excipients such as Mannitol, USP (223.75 mg); croscarmellose sodium (6.0 mg); maize starch (15.0 mg); hydroxypropylmethylcellulose (2.25 mg) and magnesium stearate (3.0 mg).
- a capsule formulation containing the above active ingredient (10 mg) for oral administration may contain pharmaceutically acceptable excipients such as mannitol, USP (488.5 mg); croscarmellose sodium (15.0 mg) and magnesium stearate (1.5 mg).
- a suitable oil formulation may also be prepared using, for example, the free base of the above compound and a 25% glycerine in water mixture. This can be used, for example, in gel caps or other suitable delivery means. The above formulations may be prepared by
- the present invention therefore relates to a pharmaceutical composition comprising an effective amount of the active compounds as described herein in admixture with known pharmaceutically acceptable carriers.
- the present invention further relates to a method for antagonizing the effects of dopamine receptor (D1 and D2) agonists or serotonin 5HT2 agonists by antagonizing the respective receptor sites comprising administering to a patient in need of treatment thereof, an antagonist amount of the compounds or compositions as described herein.
- the invention therefore also relates to a method of treating neurological disorders affected, acerbated or caused by excessive activation of D1, D2 or 5HT2 receptors comprising administering an antagonistic amount of a compound according to formula I.
- the compound (-)-1-(9,10-dihydro-9,10-methanoanthracen-9-yl-methyl)-4-(2-ethylsulfinyl)-3 pryidyl)piperidin-4-ol has good equilibrium solubility in aqueous and non-aqueous media and retains chemical and stereochemical stability in solution.
- the compound as the free amine is also advantageously non-hygroscopic.
Abstract
Description
Claims
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
HU9503554A HU219239B (en) | 1993-07-09 | 1994-07-04 | Piperidinyl substituted methanoanthracenes, process for producing them and pharmaceutical compositions containing them |
SK29-96A SK2996A3 (en) | 1993-07-09 | 1994-07-04 | Methanoanthracenes substituted by piperidinyl group, preparation method thereof and their use as d1/d2-dopamine-antagonists and 5ht2-serotonin-antagonists |
JP7503893A JP3031634B2 (en) | 1993-07-09 | 1994-07-04 | Piperidinyl-substituted methanoanthracene as D1 antagonist / D2 antagonist and 5HT2-serotonin antagonist |
NZ268048A NZ268048A (en) | 1993-07-09 | 1994-07-04 | 9-(4-hydroxypiperidylmethyl)-9,10-methanoanthracenes; pharmaceutical compositions |
RU96102585A RU2128178C1 (en) | 1993-07-09 | 1994-07-04 | Piperidinyl-substituted methanoanthracenes and their pharmaceutically acceptable salts, a pharmaceutical composition based on said and methods of their synthesis |
AU70779/94A AU687414B2 (en) | 1993-07-09 | 1994-07-04 | Piperidinyl substituted methanoanthracenes as D1/D2-antagonists and 5HT2-serotanin-antagonists |
DE69416131T DE69416131T2 (en) | 1993-07-09 | 1994-07-04 | PIPERIDINYL SUBSTITUTED METHANOANTHRACENES AS D1 / D2 ANTAGONISTS AND 5HT2 SEROTONIN ANTAGONISTS |
DK94919752T DK0707579T3 (en) | 1993-07-09 | 1994-07-04 | Piperidinyl-substituted methanoanthracenes as D1 / D2 antagonists and 5 HT2-serotanin antagonists |
EP94919752A EP0707579B1 (en) | 1993-07-09 | 1994-07-04 | Piperidinyl substituted methanoanthracenes as d1/d2-antagonists and 5ht2-serotanin-antagonists |
NO960080A NO960080L (en) | 1993-07-09 | 1996-01-08 | Piperidinyl substituted methanoanthracenes as D1 / D2 antagonists and 5HT2 serotonin antagonists |
FI960084A FI960084A (en) | 1993-07-09 | 1996-01-08 | Piperidinyl-substituted methanoanthracenes as D1 / D2 antagonists and 5HT2 serotonin antagonists |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9314250.3 | 1993-07-09 | ||
GB939314250A GB9314250D0 (en) | 1993-07-09 | 1993-07-09 | Piperidinyl compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995001974A1 true WO1995001974A1 (en) | 1995-01-19 |
Family
ID=10738563
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1994/001439 WO1995001974A1 (en) | 1993-07-09 | 1994-07-04 | Piperidinyl substituted methanoanthracenes as d1/d2-antagonists and 5ht2-serotanin-antagonists |
Country Status (26)
Country | Link |
---|---|
EP (1) | EP0707579B1 (en) |
JP (1) | JP3031634B2 (en) |
AP (1) | AP521A (en) |
AT (1) | ATE175963T1 (en) |
AU (1) | AU687414B2 (en) |
CA (1) | CA2163994A1 (en) |
CZ (1) | CZ4496A3 (en) |
DE (1) | DE69416131T2 (en) |
DK (1) | DK0707579T3 (en) |
DZ (1) | DZ1796A1 (en) |
ES (1) | ES2128567T3 (en) |
FI (1) | FI960084A (en) |
GB (2) | GB9314250D0 (en) |
HR (1) | HRP940394A2 (en) |
HU (1) | HU219239B (en) |
IL (1) | IL110222A (en) |
MY (1) | MY111604A (en) |
NO (1) | NO960080L (en) |
NZ (1) | NZ268048A (en) |
PL (1) | PL312498A1 (en) |
RU (1) | RU2128178C1 (en) |
SG (1) | SG45425A1 (en) |
SI (1) | SI9400281A (en) |
SK (1) | SK2996A3 (en) |
WO (1) | WO1995001974A1 (en) |
ZA (1) | ZA944930B (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0533344A1 (en) * | 1991-08-15 | 1993-03-24 | Zeneca Limited | Methanoanthracenes as dopamine antagonists |
-
1993
- 1993-07-09 GB GB939314250A patent/GB9314250D0/en active Pending
-
1994
- 1994-06-30 AP APAP/P/1994/000652A patent/AP521A/en active
- 1994-07-01 GB GB9413235A patent/GB9413235D0/en active Pending
- 1994-07-04 WO PCT/GB1994/001439 patent/WO1995001974A1/en not_active Application Discontinuation
- 1994-07-04 AU AU70779/94A patent/AU687414B2/en not_active Ceased
- 1994-07-04 AT AT94919752T patent/ATE175963T1/en not_active IP Right Cessation
- 1994-07-04 PL PL94312498A patent/PL312498A1/en unknown
- 1994-07-04 SG SG1996007272A patent/SG45425A1/en unknown
- 1994-07-04 CA CA002163994A patent/CA2163994A1/en not_active Abandoned
- 1994-07-04 RU RU96102585A patent/RU2128178C1/en active
- 1994-07-04 CZ CZ9644A patent/CZ4496A3/en unknown
- 1994-07-04 JP JP7503893A patent/JP3031634B2/en not_active Expired - Fee Related
- 1994-07-04 NZ NZ268048A patent/NZ268048A/en unknown
- 1994-07-04 DE DE69416131T patent/DE69416131T2/en not_active Expired - Lifetime
- 1994-07-04 EP EP94919752A patent/EP0707579B1/en not_active Expired - Lifetime
- 1994-07-04 HU HU9503554A patent/HU219239B/en not_active IP Right Cessation
- 1994-07-04 ES ES94919752T patent/ES2128567T3/en not_active Expired - Lifetime
- 1994-07-04 SK SK29-96A patent/SK2996A3/en unknown
- 1994-07-04 DK DK94919752T patent/DK0707579T3/en active
- 1994-07-05 IL IL11022294A patent/IL110222A/en not_active IP Right Cessation
- 1994-07-06 HR HR9314250.3A patent/HRP940394A2/en not_active Application Discontinuation
- 1994-07-07 ZA ZA944930A patent/ZA944930B/en unknown
- 1994-07-08 SI SI9400281A patent/SI9400281A/en unknown
- 1994-07-09 DZ DZ940075A patent/DZ1796A1/en active
- 1994-07-09 MY MYPI94001799A patent/MY111604A/en unknown
-
1996
- 1996-01-08 NO NO960080A patent/NO960080L/en not_active Application Discontinuation
- 1996-01-08 FI FI960084A patent/FI960084A/en unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0533344A1 (en) * | 1991-08-15 | 1993-03-24 | Zeneca Limited | Methanoanthracenes as dopamine antagonists |
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